Privigen PRODUCT MONOGRAPH. Immune Globulin Intravenous (Human) 10 % Solution for infusion. Passive Immunizing Agent

Transcription

1 PRODUCT MONOGRAPH Privigen Immune Globulin Intravenous (Human) 10 % Solution for infusion Passive Immunizing Agent CSL Behring Canada, Inc. 55 Metcalfe Street, Suite 1460 Ottawa, Ontario K1P 6L5 Date of Preparation: December 22, 2017 Date of Approval: January 02, 2018 Submission Control No.: Page 1 of 40

2 Table of Contents PART I: HEALTH PROFESSIONAL INFORMATION... 3 SUMMARY PRODUCT INFORMATION... 3 DESCRIPTION... 3 INDICATIONS AND CLINICAL USE... 3 CONTRAINDICATIONS... 4 WARNINGS AND PRECAUTIONS... 4 ADVERSE REACTIONS DRUG INTERACTIONS DOSAGE AND ADMINISTRATION OVERDOSAGE ACTION AND CLINICAL PHARMACOLOGY STORAGE AND STABILITY SPECIAL HANDLING INSTRUCTIONS DOSAGE FORMS, COMPOSITION AND PACKAGING PART II: SCIENTIFIC INFORMATION PHARMACEUTICAL INFORMATION CLINICAL TRIALS DETAILED PHARMACOLOGY MICROBIOLOGY TOXICOLOGY REFERENCES PART III: CONSUMER INFORMATION Page 2 of 40

3 Privigen Immune Globulin Intravenous (Human) PART I: HEALTH PROFESSIONAL INFORMATION SUMMARY PRODUCT INFORMATION Route of Administration Dosage Form / Strength Intravenous 10% Solution for infusion L-proline DESCRIPTION Clinically Relevant Nonmedicinal Ingredients For a complete listing see Dosage form, Composition and Packaging section. Privigen, Immune Globulin Intravenous (Human), is a ready-to-use, sterile, 10% protein liquid preparation of polyvalent human immunoglobulin G (IgG) for intravenous administration. Privigen is prepared from large pools of human plasma by a combination of cold ethanol fractionation, octanoic acid fractionation, combined with a filter aid-assisted depth filtration, and anion exchange chromatography. The Privigen manufacturing process includes an immunoaffinity chromatography step that specifically reduces blood group A and B antibodies (isoagglutinins A and B) (see section PHARMACEUTICAL INFORMATION). INDICATIONS AND CLINICAL USE Privigen (Immune Globulin Intravenous (Human)) is indicated for: The treatment of patients with primary immune deficiency (PID) and secondary immune deficiency (SID). This includes, but is not limited to, common variable immunodeficiency (CVID), X-linked agammaglobulinemia, congenital agammaglobulinemia, secondary hypogammaglobulinemia, Wiskott-Aldrich syndrome, and severe combined immunodeficiencies. The treatment of patients with immune thrombocytopenic purpura (ITP) to rapidly raise platelet counts to prevent bleeding. Immunomodulation in patients with chronic inflammatory demyelinating polyneuropathy (CIDP). Geriatrics: See subsection Special Populations, under section WARNINGS AND PRECAUTIONS. Pediatrics: See subsection Special Populations, under section WARNINGS AND PRECAUTIONS. Page 3 of 40

4 CONTRAINDICATIONS Privigen, Immune Globulin Intravenous (Human), is contraindicated in individuals with selective IgA deficiency with known anti-iga antibodies. Privigen contains trace amounts of no more than 25 mcg/ml of IgA levels. Privigen is contraindicated in patients who have had an anaphylactic or severe systemic reaction to the administration of human immune globulin. WARNINGS AND PRECAUTIONS Serious Warnings and Precautions Intravenous Immune Globulin (Human) (IVIG) products have been reported to be associated with renal dysfunction, acute renal failure, osmotic nephrosis, and death. 1 Patients predisposed to acute renal failure include patients with any degree of pre-existing renal insufficiency, diabetes mellitus, age greater than 65, volume depletion, sepsis, paraproteinemia, or patients receiving known nephrotoxic drugs. In such patients, IVIG products should be administered at the minimum rate of infusion practicable. While these reports of renal dysfunction and acute renal failure have been associated with the use of many of the licensed IVIG products, those containing sucrose as a stabilizer accounted for a disproportionate share of the total number. Privigen does not contain carbohydrates as stabilizers (e.g., sucrose, maltose) (see sections DOSAGE AND ADMINISTRATION and WARNINGS AND PRECAUTIONS for important information intended to reduce the risk of acute renal failure). There is clinical evidence of an association between the administration of immunoglobulins and thromboembolic events such as myocardial infarction, stroke, pulmonary embolism and deep vein thrombosis. Therefore, caution should be exercised when prescribing and administering immunoglobulins. Risk factors for thromboembolic events include: advanced age, use of estrogens, in-dwelling central vascular catheters, history of vascular disease or thrombotic episodes, acquired or inherited hypercoagulable states, prolonged periods of immobilization, severe hypovolemia, diseases which increase blood viscosity and cardiovascular risk factors (including obesity, hypertension, diabetes mellitus). Thrombosis may occur even in the absence of known risk factors (see WARNING AND PRECAUTIONS Thromboembolism sub-section.) Page 4 of 40

5 General Privigen, Immune Globulin Intravenous (Human), is made from human plasma. Products made from human plasma may contain infectious agents, e.g., viruses, and theoretically the Creutzfeldt- Jakob disease (CJD) agent, that can cause disease. The risk that such products will transmit an infectious agent has been reduced by screening plasma donors for prior exposure to certain viruses, by testing for the presence of certain current virus infections, and by removing certain viruses during manufacturing through a four step process: octanoic acid fractionation combined with a filter aid-assisted depth filtration, virus filtration and inactivation by ph 4 incubation as well as additional depth filtration (see subsection Viral Inactivation/Removal under section PHARMACEUTICAL INFORMATION). Despite these measures, such products can still potentially transmit disease. There is also the possibility that unknown infectious agents may be present in such products. All infections thought by a physician possibly to have been transmitted by this product should be reported by the physician or other healthcare provider to CSL Behring at The physician should discuss the risks and benefits of this product with the patient. Because Privigen contains the stabilizer L-proline, caution should be considered in patients with hyperprolinemia (type I and II). Physicians should weigh the risk/benefit of use in these patients on an individual basis. Hypersensitivity True hypersensitivity reactions are rare. They can occur in patients with anti-iga antibodies. IVIG is not indicated in patients with selective IgA deficiency where the IgA deficiency is the only abnormality of concern. Rarely, human normal immunoglobulin can cause a fall in blood pressure with anaphylactoid reaction, even in patients who had tolerated previous treatment with human normal immunoglobulin. Thromboembolism Thromboembolic events such as myocardial infraction, stroke, pulmonary embolism and deep vein thrombosis have been associated with the use of immunoglobulins. Since thrombosis may occur in the absence of known risk factors, caution should be exercised in prescribing and administering immunoglobulins. Privigen should be administered at the minimum dose and at the minimum rate of infusion practicable. Patients should be adequately hydrated before administration of immunoglobulins. Baseline assessment of blood viscosity should be considered in patients at risk for hyperviscosity, including those with cryoglobulins, fasting chylomicronemia/markedly high triacylglycerols (triglycerides), or monoclonal gammopathies. Patients at risk of hyperviscosity should be monitored for signs and symptoms of thrombosis and blood viscosity assessed. Page 5 of 40

6 Risk factors for thromboembolic events include: advanced age, use of estrogens, in-dwelling central vascular catheters, history of vascular disease or thrombotic episodes, acquired or inherited hypercoagulable states, prolonged periods of immobilization, severe hypovolemia, diseases which increase blood viscosity and cardiovascular risk factors (including obesity, hypertension, diabetes mellitus). Hematologic IVIG products can contain blood group antibodies (e.g. isoagglutinins A and B) that may act as hemolysins and induce in vivo coating of red blood cells (RBCs) with immunoglobulin, causing a positive direct antiglobulin reaction 5-7 and rarely, hemolysis. The Privigen manufacturing process includes an immunoaffinity chromatography step (IAC) that specifically reduces blood group A and B antibodies (isoagglutinins A and B). Clinical data with Privigen manufactured with the IAC step is not yet available. Delayed hemolytic anemia can develop subsequent to Privigen therapy due to enhanced RBC sequestration, and acute hemolysis, consistent with intravascular hemolysis, has been reported 8. Isolated cases of hemolysis-related renal dysfunction/failure or disseminated intravascular coagulation have occurred. The following risk factors may be associated with the development of hemolysis: high doses, whether given as a single administration or divided over several days; non-o blood group; and underlying inflammatory state. 9 As this event was commonly reported in non-o blood group patients receiving high doses for non-pid/sid indications, increased vigilance is recommended. Hemolysis has rarely been reported in patients given replacement therapy for PID/SID. Hemolysis, possibly intravascular, occurred in two subjects treated with Privigen in the ITP study. These cases resolved uneventfully. Six other subjects experienced hemolysis in the ITP study as documented from clinical laboratory data. IVIG recipients should be closely monitored for clinical signs and symptoms of hemolysis. If signs and/or symptoms of hemolysis are present after IVIG infusion, appropriate confirmatory laboratory testing should be performed. If transfusion is indicated for patients who develop hemolytic anemia after receiving IVIG, cross-matching should be performed. Page 6 of 40

7 Neurologic Aseptic Meningitis Syndrome (AMS) has been reported to occur infrequently in association with IVIG treatment. The syndrome usually begins within several hours to 2 days following IVIG treatment. AMS is characterized by signs and symptoms including severe headache, nuchal rigidity, drowsiness, fever, photophobia, painful eye movements, nausea, and vomiting. Cerebrospinal fluid (CSF) studies are frequently positive with pleocytosis up to several thousand cells per cubic millimeter, predominantly from the granulocyte series, and with elevated protein levels up to several hundred mg/dl. Patients exhibiting such signs and symptoms should receive a thorough neurological examination, including CSF studies, to rule out other causes of meningitis. AMS may occur more frequently in association with high doses ( 2 g/kg bw) and/or rapid infusion of IVIG. Discontinuation of IVIG treatment has resulted in remission of AMS within several days without sequelae. 10 Renal Acute renal dysfunction/failure, osmotic nephropathy, and death may occur with the use of IVIG products, particularly those containing sucrose. 1 Privigen does not contain any sugar such as sucrose, maltose or glucose. Patients should not be volume depleted prior to the initiation of the infusion of Privigen. Periodic monitoring of renal function and urine output is particularly important in patients judged to have a potential increased risk of developing acute renal failure. Renal function, including measurement of blood urea nitrogen (BUN) and serum creatinine, should be assessed before the initial infusion of Privigen and at appropriate intervals thereafter. For patients judged to be at risk of developing renal dysfunction because of pre-existing renal insufficiency, or predisposition to acute renal failure (such as those with diabetes mellitus, sepsis, paraproteinemia, or hypovolemia, those who are obese, those who use concomitant nephrotoxic medicinal products, or those who are over 65 years of age), Privigen should be administered at the minimum rate of infusion practicable (see section DOSAGE AND ADMINISTRATION). If renal function deteriorates, consider discontinuing Privigen. Respiratory There have been reports of noncardiogenic pulmonary edema in patients administered IVIG. 11 Transfusion-related Acute Lung Injury (TRALI) is characterized by severe respiratory distress, pulmonary edema, hypoxemia, normal left ventricular function, and fever and typically occurs within 1 to 6 hours following transfusion. IVIG recipients should be monitored for pulmonary adverse reactions. Patients with TRALI may be managed using oxygen therapy with adequate ventilatory support. If TRALI is suspected, appropriate tests should be performed for the presence of antineutrophil antibodies in both product and the patient s serum. Page 7 of 40

8 Special Populations Pregnant Women: The safety of Privigen for use in human pregnancy has not been established in controlled clinical trials. IVIG products have been shown to cross the placenta, increasingly during the third trimester. Privigen should only be used in pregnant women when the benefits outweigh the risks associated with its use. Nursing Women: Immunoglobulins are excreted into the milk and may contribute to protecting the neonate from pathogens which have a mucosal portal of entry. Privigen should only be used in nursing women when the benefits outweigh the risk associated with its use. Fertility: No human data are available to indicate the presence or absence of drug associated risk. Animal reproduction studies have not been conducted with Privigen. Pediatrics (3-16 years of age): Treatment of Primary and Secondary Immune Deficiency In the pivotal study, Privigen was evaluated in 31 pediatric subjects (19 children and 12 adolescents) with PID. In the extension study, there were 21 pediatric subjects evaluated (13 children and 8 adolescents) of which 19 were carried forward from the pivotal study. There were no apparent differences in the safety and efficacy profiles as compared to adult subjects. No pediatric-specific dose requirements were necessary to achieve the desired serum IgG levels. The safety and efficacy of Privigen has not been established in pediatric subjects with PID who are under the age of 3. Treatment of Immune Thrombocytopenic Purpura The safety and effectiveness of Privigen has not been established in pediatric subjects with ITP, who are under the age of 15. Treatment of Chronic Inflammatory Demyelinating Polyneuropathy The safety and effectiveness of Privigen has not been established in pediatric subjects with CIDP, who are under the age of 18. However, the dosage and administration in children and adolescents should not differ from that of adults as the dosage for each indication is given by body weight and adjusted to the clinical outcome. Geriatrics: Privigen should be used with caution in patients over 65 years of age who are judged to be at increased risk of developing renal insufficiency (see Warnings and Precautions under section WARNINGS AND PRECAUTIONS). For those patients with the risk of renal insufficiencies, Privigen must be infused at the minimum practicable rate. Page 8 of 40

9 Clinical studies of Privigen did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Monitoring and Laboratory Tests The patient s vital signs should be observed and monitored carefully throughout the infusion. If side effects occur, the infusion should be slowed or stopped until the symptoms subside. The infusion may then be resumed at a lower rate that is comfortable for the patient. After infusion of IgG, the transitory rise of the various passively transferred antibodies in the patient s blood may yield positive serological testing results, with the potential for misleading interpretation. Passive transmission of antibodies to erythrocyte antigens (e.g., A, B, and D) may cause a positive direct or indirect antiglobulin (Coombs ) test. Page 9 of 40

10 ADVERSE REACTIONS Adverse Drug Reaction Overview In clinical trials undertaken with Privigen, Immune Globulin Intravenous (Human), the most serious adverse reaction observed in patients receiving Privigen for the PID was hypersensitivity in one subject. The most serious adverse reactions observed in patients receiving Privigen for ITP were aseptic meningitis syndrome in one subject and anemia in two other ITP subjects (see section WARNINGS AND PRECAUTIONS). The most serious adverse reactions observed in patients receiving Privigen for CIDP were Hemolysis in two subjects. The most common adverse reaction observed for PID, ITP and CIDP was headache. In general, reported adverse reactions to Privigen in subjects with PID, ITP or CIDP were similar in kind and frequency to those observed with other IVIG products. Clinical Trial Adverse Drug Reactions Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in practice. Treatment of Primary and Secondary Immune Deficiency Pivotal study In a prospective, open-label, single-arm, multicenter clinical study, 80 subjects with PID received median doses of Privigen ranging from 200 to 888 mg/kg bw every 3 weeks (median dose mg/kg bw) or 4 weeks (median dose mg/kg bw) for up to 12 months (see section CLINICAL TRIALS). Routine premedication was not allowed. However, subjects who experienced two consecutive infusion-related adverse events (AEs) that were likely to be prevented by premedication were permitted to receive antipyretics, antihistamines, NSAIDs, or antiemetic agents. During the study, 8 (10%) subjects received premedication prior to 51 (4.9%) of the 1038 infusions administered. The safety endpoint of the study was the proportion of infusions with one or more temporally associated AEs. Temporally associated AEs are those occurring during or within 72 hours after the end of an infusion, irrespective of causality. A target for this safety endpoint is an upper 1-sided confidence limit of less than 40%. In this study, the upper bound of the 1-sided 97.5% confidence interval for the proportion of Privigen infusions with temporally associated AEs was 23.8%, thus well below the target for this safety endpoint. Page 10 of 40

11 Table 1 summarizes the proportion of Privigen infusions resulting in temporally associated AEs and the number and rate of temporally associated AEs, irrespective of causality. Table 1: Privigen Infusions With Temporally Associated Adverse Events* (TAAEs) in Subjects With PID, Irrespective of Causality TAAEs* occurring during or within the Total number of infusions: 1038 specified number of hours after the end of an infusion 24 hours 48 hours 72 hours Proportion of infusions with TAAEs 16% 19% 21% Upper bound of 1-sided 97.5% confidence interval for the 18.7% 21.5% 23.8% proportion of infusions with TAAEs Total number of TAAEs Rate of TAAEs (per total number of infusions) *Including infections. Table 2 lists the temporally associated AEs that occurred in more than 5% of subjects during or within 72 hours after the end of a Privigen infusion, irrespective of causality. Table 2: Temporally Associated Adverse Events* (TAAEs) in >5% of Subjects With PID During or Within 72 Hours After the End of an Privigen Infusion, Irrespective of Causality TAAE* Subjects (%) Infusions (%) (n=80) (n=1038) Headache 35 (43.8) 90 (8.7) Fatigue 13 (16.3) 29 (2.8) Nausea 10 (12.5) 22 (2.1) Chills 9 (11.3) 15 (1.4) Back pain 8 (10.0) 14 (1.3) Pain 7 (8.8) 14 (1.3) Vomiting 7 (8.8) 13 (1.3) Pyrexia 6 (7.5) 11 (1.1) Cough 5 (6.3) 5 (0.5) Diarrhea 5 (6.3) 5 (0.5) Stomach discomfort 5 (6.3) 5 (0.5) *Excluding infections. Page 11 of 40

12 Table 3 lists the related temporally associated AEs that occurred in more than 5% of subjects with PID during or within 72 hours after the end of a Privigen infusion. Related AEs were defined as those judged by the investigators to be at least possibly causally related to the infusion of Privigen. Table 3: Related Temporally Associated Adverse Events (TAAEs) in >5% of Subjects With PID During or Within 72 Hours After the End of a Privigen Infusion Related TAAE Subjects (%) Infusions (%) (n=80) (n=1038) Headache 23 (28.8) 64 (6.2) Nausea 9 (11.3) 20 (1.9) Fatigue 9 (11.3) 18 (1.7) Chills 9 (11.3) 15 (1.4) Pain 5 (6.3) 9 (0.9) Sixteen subjects (20%) experienced 38 serious AEs. Five of these were severe AEs (hypersensitivity, chills, fatigue, dizziness, and increased body temperature) that occurred in one subject. All five were related to Privigen and resulted in the subject s withdrawal from the study. Two other subjects withdrew from the study due to AEs related to Privigen (chills and headache in one subject; vomiting in the other). One subject died due to multiple organ system failure, which was not related to Privigen. Of the 1330 AEs reported, the investigators judged 215 to be related to the infusion of Privigen (including the five serious, severe AEs described above). Of the 210 non-serious AEs, 104 were mild, 89 were moderate, 16 were severe, and 1 was not ranked ( unknown ). During this study, no subjects tested positive for infection due to human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV), or B19 virus (B19V). Extension study During an extension of the pivotal study, higher infusion rates were permitted and additional efficacy, safety and tolerability data were collected. This study included original subjects from the pivotal study (n=45) and new subjects who were previously receiving another IVIG product (n=10). Only subjects who continued from the pivotal study were permitted to receive a Higher Infusion Rate (HIR) at the discretion of the investigator. Twenty-three of 45 subjects (51.1%) received 265 (38.4%) infusions at a maximum rate greater than 8 mg/kg/min (median: 12 mg/kg/min; maximum: 16 mg/kg/min) with 97% of infusions in the HIR group reaching a maximum infusion rate of 12 mg/kg/min. When analyzed by infusion rate class (i.e., LIR vs. HIR), the proportion of infusions with TAAEs (72 hours) was considerably lower with HIR infusions than with LIR infusions (0.072 vs ), as was also seen in the rate of TAAEs per infusion. Overall, this reflects both the study design and the clinical practice to increase the infusion rate according to patient tolerance. Page 12 of 40

13 Twenty-two subjects remained on the high infusion rate; one subject withdrew from the study due to urticaria, which was mild, but was considered drug-related. Due to the small population size in the clinical trial, the safety and tolerability of Privigen administered at a higher infusion rate of 12mg/kg/min should be monitored by users. Treatment of Immune Thrombocytopenic Purpura In a prospective, open-label, single-arm, multicenter clinical study, 57 subjects with ITP received a 2 g/kg bw dose of Privigen administered as two 1 g/kg bw intravenous infusions on two consecutive days (see section CLINICAL TRIALS). Two of the 57 ITP subjects experienced hemolysis. These cases resolved uneventfully. Six other subjects experienced laboratory signs for hemolysis without clinical relevance. All 8 subjects developed a transient positive direct Coombs test. Concomitant medications affecting platelets or other treatments for ITP were not allowed. Thirtytwo (56.1%) subjects received premedication with acetaminophen and/or an antihistamine. Table 4 lists the temporally associated AEs that occurred in more than 5% of subjects with ITP during or within 72 hours after the end of a treatment cycle (two consecutive infusions) with Privigen, irrespective of causality. Table 4: Temporally Associated Adverse Events (TAAEs) in >5% Subjects With ITP During or Within 72 Hours After the End of a Treatment Cycle* With Privigen, Irrespective of Causality TAAE Subjects (%) (n=57) Headache 37 (64.9) Pyrexia 14 (24.6) Nausea 6 (10.5) Vomiting 6 (10.5) Epistaxis 6 (10.5) Hyperthermia 5 (8.8) Bilirubin conjugated increased 5 (8.8) Blood bilirubin unconjugated increased 5 (8.8) Hyperbilirubinemia 3 (5.3) Hematocrit decreased 3 (5.3) * Two consecutive infusions. Page 13 of 40

14 Table 5 lists all related AEs that occurred in more than 5% of subjects with ITP during and/or following a treatment cycle with Privigen. Related AEs were defined as those judged by the investigators to be at least possibly causally related to the infusion of Privigen. Table 5: Related Adverse Events* in >5% of Subjects With ITP During and/or Following a Treatment Cycle With Privigen Related AE* Subjects (%) (n=57) Headache 37 (64.9) Pyrexia 14 (24.6) Anemia 6 (10.5) Hyperthermia 5 (8.8) Nausea 5 (8.8) Vomiting 5 (8.8) Bilirubin conjugated increased 5 (8.8) Blood bilirubin unconjugated increased 5 (8.8) Blood lactate dehydrogenase increased 3 (5.3) Coombs direct test positive 3 (5.3) Coombs test positive 3 (5.3) Hematocrit decreased 3 (5.3) Hyperbilirubinemia 3 (5.3) * Includes all related AEs, including those beyond 72 hours after end of last infusion. Two consecutive infusions. Three subjects experienced three serious AEs, one of which (aseptic meningitis) was related to the infusion of Privigen. One subject withdrew from the study due to gingival bleeding, which was not related to Privigen. Two subjects experienced transient drug-related non-serious hemolytic reactions manifested as anemia and a positive direct Coombs test. Of the 270 AEs reported, 256 (94.8%) were mild to moderate in severity and transient in nature. The investigators judged 174 of the 270 AEs reported to be related to the infusion of Privigen. In a prospective, multicenter, open-label, single-arm study to investigate the efficacy and safety of Privigen in the treatment of CIDP, 28 patients received Privigen induction dose of 2 g/kg bw divided over 2 to 5 consecutive days, followed by 6 maintenance doses of 1 g/kg bw over 1 to 2 consecutive days every 3 weeks (see Section CLINICAL TRIALS). AEs occurred after 108 of the 259 infusions administered in this study, resulting in an AE rate per infusion of The rate of AEs that were considered at least possibly related to the study drug was (49 events). The rate of temporally associated AEs occurring between the start of an infusion and within 72 h after the end of infusion was (66 events). No infusion had to be stopped due to an AE. Page 14 of 40

15 Four subjects experienced a total of 4 SAEs (hemolysis in two subjects; deterioration of CIDP in one subject and worsening of chronic sigmoid diverticulitis in one subject). The SAE of deterioration of CIDP started before the first infusion of Privigen. The 2 hemolysis cases (0.008 case per infusion), were considered by the investigator to be at least possibly related to the study product. Both cases were observed in the induction phase of the study, at the dose of 2 g/kg bw. There were no cases of hemolysis in the maintenance phase of the study, at a dose of 1g/kg bw. Please refer to section WARNINGS AND PRECAUTIONS for additional details on the risk factors. Of these 4 observed SAEs, one SAE (hemolysis) was severe in intensity, one SAE was moderate in intensity (chronic inflammatory demyelinating polyradiculoneuropathy), and two SAEs were mild in intensity (hemolysis and diverticulitis). All SAEs resolved without sequelae. There were no deaths in this Study. Table 6 lists the temporally associated AEs occurring during an infusion or within 72 h after the end of infusion in more than 5% of subjects. Table 6: Temporally Associated Adverse Events in >5% Subjects with CIDP (Within 72 h), Irrespective of Causality TAAE Subjects (%) (n=28) Infusions (%) (n=259) Headache 8 (28.6) 19 (0.073) Hypertension 4 (14.3) 6 (0.023) Asthenia 4 (14.3) 4 (0.015) Pain in extremity 3 (10.7) 3 (0.012) Nausea 3 (10.7) 3 (0.012) Influenza like 2 (7.1) 2 (0.008) illness Hemolysis 2 (7.1) 2 (0.008) Page 15 of 40

16 The most common AE considered to be at least possibly related overall during the study was headache, which was reported by 8 subjects (28.6%) in total (7 subjects [25.0%] during induction period; 4 subjects [14.3%] during maintenance period). Table 7: Related Adverse Events in >5% of Subjects With CIDP during treatment period (Induction Period, Maintenance Period and Total) Preferred term Induction period Maintenance period Total Number (%) of subjects (N=28) Number of AEs (rate per infusion) (N=73) Number (%) of subjects (N=28) Number of AEs (rate per infusion) (N=186) Number (%) of subjects (N=28) Number of AEs (rate per infusion) (N=259) Any preferred term 13 (46.4) 27 (0.370) 11 (39.3) 22 (0.118) 17 (60.7) 49 (0.189) Headache 7 (25.0) 7 (0.096) 4 (14.3) 11 (0.059) 8 (28.6) 18 (0.069) Hypertension 3 (10.7) 3 (0.041) 2 (7.1) 2 (0.011) 4 (14.3) 5 (0.019) Asthenia 3 (10.7) 3 (0.041) 1 (3.6) 1 (0.005) 4 (14.3) 4 (0.015) Nausea 2 (7.1) 2 (0.027) 1 (3.6) 1 (0.005) 3 (10.7) 3 (0.012) Influenza-like illness 2 (7.1) 2 (0.027) (7.1) 2 (0.008) Hemolysis 2 (7.1) 2 (0.027) (7.1) 2 (0.008) Leukopenia (7.1) 2 (0.011) 2 (7.1) 2 (0.008) Rash 1 (3.6) 1 (0.014) 1 (3.6) 1 (0.005) 2 (7.1) 2 (0.008) AE = Adverse event;; N = Total number of subjects or infusions in the study. Page 16 of 40

17 Post-Market Adverse Drug Reactions Privigen The following adverse reactions have been identified during post-marketing use of Privigen: Infusion reactions: Hypersensitivity (e.g., anaphylactic shock, anaphylaxis), changes in blood pressure, dyspnea, chills and fever, tachycardia, chest discomfort/pain, flushing Hematologic: Hemolytic anemia, jaundice/hyperbilirubinemia, hemoglobinuria/hematuria/chromaturia, acute renal failure Neurological: Headache, aseptic meningitis, photophobia, dizziness Integumentary: Urticaria, pruritus, rash Respiratory: Transfusion-related Acute Lung Injury (TRALI) General The following adverse reactions have been identified and reported during the post approval use of immune globulin products. 12 Infusion Reactions: Hypersensitivity (e.g., anaphylaxis), headache, diarrhea, tachycardia, fever, fatigue, dizziness, malaise, chills, flushing, urticaria or other skin reactions, wheezing or other chest discomfort, nausea, vomiting, rigors, back pain, myalgia, arthralgia, and changes in blood pressure Respiratory: Apnea, Acute Respiratory Distress Syndrome (ARDS), TRALI, cyanosis, hypoxemia, pulmonary edema, dyspnea, bronchospasm Cardiovascular: Cardiac arrest, thromboembolism, vascular collapse, hypotension Neurological: Coma, loss of consciousness, seizures, tremor, aseptic meningitis Integumentary: Stevens-Johnson syndrome, epidermolysis, erythema multiforme, bullous dermatitis Hematologic: Pancytopenia, leukopenia, hemolysis, positive direct antiglobulin (Coombs ) test, haemolytic anaemia General/Body as a Whole: Pyrexia, rigors Musculoskeletal: Back pain Gastrointestinal: Hepatic dysfunction, abdominal pain Because postmarketing reporting of adverse reactions is voluntary and from a population of uncertain size, it is not always possible to reliably estimate the frequency of these reactions or establish a causal relationship to drug exposure. Evaluation and interpretation of these postmarketing reactions is confounded by underlying diagnosis, concomitant medications, preexisting conditions, and inherent limitations of passive surveillance. Page 17 of 40

18 DRUG INTERACTIONS Overview Immunoglobulin administration may transiently impair the efficacy of live attenuated virus vaccines such as measles, mumps, rubella and varicella/chickenpox for a period of at least 6 weeks and up to 3 months. An interval of 3 months should elapse before vaccination with live attenuated vaccines. In the case of measles vaccinations, the decrease in efficacy may persist for up to a year. Patients given measles vaccine should therefore have their antibody status checked.the immunizing physician should be informed of recent therapy with Privigen so that appropriate measures may be taken. Drug-Drug Interactions See subsection Overview. Drug-Food Interactions Interactions with food have not been established. Drug-Herb Interactions Interactions with herbal products have not been established. Drug-Laboratory Interactions See subsection Monitoring and Laboratory Tests under section WARNINGS AND PRECAUTIONS. Page 18 of 40

19 DOSAGE AND ADMINISTRATION Ensure that patients with pre-existing renal insufficiency and those predisposed to acute renal failure are not volume depleted before administering Privigen, Immune Globulin Intravenous (Human) (see section WARNINGS AND PRECAUTIONS). The patient s vital signs should be observed and monitored carefully throughout the infusion. If side effects occur, the infusion should be slowed or stopped. If the symptoms subside promptly, the infusion may then be resumed at a lower rate that is comfortable for the patient. The treatment required depends on the nature and severity of the adverse reaction. In case of shock, standard medical measures for shock should be implemented. Recommended Dose and Dosage Adjustment Treatment of Primary and Secondary Immune Deficiency The usual dose of Privigen for patients with PID and SID is 200 to 800 mg/kg body weight (bw), administered every 3 to 4 weeks. A target serum immunoglobulin G (IgG) trough level of at least 5 g/l has been proposed. 13, 14 However, an optimum level in patients with PID/SID has not been established in randomized, controlled clinical studies. Doses should be adjusted to achieve the desired serum trough levels and clinical responses. Treatment of Immune Thrombocytopenic Purpura The usual dose of Privigen for patients with ITP is 1 g/kg bw administered for 2 consecutive days, resulting in a total dosage of 2 g/kg bw. Treatment of Chronic Inflammatory Demyelinating Polyneuropathy The recommended starting dose * is 2 g/kg bw divided over 2 to 5 consecutive days followed by maintenance doses of 1 g/kg bw over 1 to 2 consecutive days every 3 weeks. Missed Dose A missed dose should be administered as soon as possible to ensure an adequate IgG serum level. * The dose is based on the dose used in the clinical study conducted with Privigen. The duration of treatment beyond 24 weeks should be subject to the physician s discretion based upon the patient response and maintenance response in the long-term. The dosing and intervals may have to be adapted according to the individual course of the disease. Page 19 of 40

20 Administration Infusion Rate The recommended initial infusion rate of Privigen is 0.5 mg/kg/min (0.3 ml/kg/hr). If well tolerated, the rate of administration may gradually be increased up to an infusion rate of 12 mg/kg/min (7.2 ml/kg/hr). As with other IgG products, patients who are receiving IgG for the first time, who have received another IgG, or who have not received IgG in more than 8 weeks may be at risk of developing systemic reactions (mimicking symptoms of an inflammatory response or infection) on rapid infusion of Privigen (greater than 4 mg/kg/min [2.4 ml/kg/hr]). These patients should be started at a slow rate of infusion (e.g., 0.5 mg/kg/min [0.3 ml/kg/hr] or less) for at least 30 min. and gradually advanced to the maximum rate as tolerated. When high doses ( 1g/kg bw) are administered it is recommended not to exceed the rate of 8 mg/kg/min.the initial infusion rate for patients who have previously received Privigen for three or more consecutive infusions can be individualized based on the rate the patient previously tolerated. For patients judged to be at risk of renal dysfunction or thrombotic events, Privigen should be administered at the minimum infusion rate practicable (see section WARNINGS AND PRECAUTIONS). Infusion Parameters Privigen is for intravenous administration and should be given by a separate infusion line. An infusion pump may be used to control the rate of administration. Do not mix Privigen with other IVIG products or other intravenous medications. If necessary, Privigen can be diluted with D5W. As well Privigen can be flushed with D5W or 0.9% Sodium Chloride for injection, USP. If large doses of Privigen are to be administered, several vials may be pooled using aseptic technique. Because the solution contains no preservative, discard partially used product after 24 hours. Reconstitution Not applicable. Privigen is a ready to use solution of human immunoglobulin for intravenous infusion. OVERDOSAGE Overdose can lead to fluid volume overload and hyperviscosity, particularly in patients at risk, including elderly patients or patients with cardiac or renal impairment. Page 20 of 40

21 ACTION AND CLINICAL PHARMACOLOGY Mechanism of Action Treatment of Primary and Secondary Immune Deficiency Privigen, Immune Globulin Intravenous (Human), contains a broad spectrum of antibody specificities against bacterial, viral, parasitic, and mycoplasma agents that are capable of both opsonization and neutralization of pathogens and toxins. Appropriate doses of Privigen should restore abnormally low IgG levels to the normal range. Treatment of Immune Thrombocytopenic Purpura The mechanism of action of immunoglobulins in the treatment of ITP is not fully understood. One possible mechanism may be the inhibition of the elimination of autoantibody-reacted platelets from the blood circulation by IgG-induced Fc-receptor blockade of phagocytes. 15 Another proposed mechanism is the down-regulation of platelet autoantibody-producing B cells by antiidiotypic antibodies in IVIG. 16 Treatment of Chronic Inflammatory Demyelinating Polyneuropathy CIDP is an immune-mediated disease and is characterized by progressive or relapsing motor and/or sensory symptoms and signs in more than 1 limb, developing over at least 2 months. Sensory disturbances are usually slight, but are a common finding in CIDP subjects. Proximal and distal parts of the limbs are usually affected symmetrically. Atrophy is less marked than weakness. Loss of reflexes is found in almost all subjects, but may be confined to the ankles. Cranial nerve involvement, sometimes preceding the neuropathy, has been reported infrequently. IVIG are beneficial in treating neuropathies by suppressing the immune-mediated processes that are directed against myelin or axonal antigenic targets. Although no specific mechanism of action has conclusively been proven to be the dominating pathway it appears that there are several possible modes of action that act together, essentially the inhibition of the complement pathway, Fc receptor modulation on macrophages (e.g inhibition of FcyRI and III or upregulation of FcyRII) inhibits macrophage-mediated demyelination, the suppression of pathogenic cytokines, the interaction with intercellular adhesion molecules to modulate cell migration, T-cell modulation and direct effects on remyelination. Page 21 of 40

22 Pharmacokinetics Treatment of Primary and Secondary Immune Deficiency In the clinical study assessing the efficacy and safety of Privigen in 80 subjects with PID (see section CLINICAL TRIALS), serum concentrations of total IgG and IgG subclasses were measured in 25 subjects (ages 12 to 65) following the 7 th infusion for the 3 subjects on the 3-week dosing interval and following the 5 th infusion for the 22 subjects on the 4-week dosing interval. Blood samples were taken 10 to 30 minutes before the infusion and 3 to 20 minutes, 24±2 hours, 3 days, 7 days, 10 days, 14±1 days, and 21±1 days after the infusion. For subjects on the 4-week dosing interval, an additional sample was taken 28±1 days after the infusion. Table 8 presents the pharmacokinetic parameters of Privigen, measured as serum concentrations of total IgG. Table 8: Pharmacokinetic Parameters of Privigen Parameter No. of Subjects Median (Range) C max (peak, mg/dl) ( ) C min (trough, mg/dl) ( ) t ½ (days) ( ) AUC 0-t (day mg/dl)* 3-week dosing interval 3 29,860 (28,580-40,010) 4-week dosing interval 22 36,670 (19,680-44,340) C max, maximum serum concentration; C min, trough (minimum level) serum concentration; t ½, elimination half-life; AUC 0-t, area under the curve from 0 hour to last sampling time. * Calculated by log-linear trapezoidal rule. The median half-life of Privigen of 36.6 days is representative of half-lives in the PID patient population receiving immunoglobulins. The IgG subclass levels observed in the pharmacokinetic population were consistent with a physiologic distribution pattern (mean trough values): IgG 1, mg/dl; IgG 2, mg/dl; IgG 3, mg/dl; IgG 4, mg/dl. In the extension study, mean trough levels of total IgG serum concentrations achieved in subjects with PID were 1115 ± 297 mg/dl for the 3-week dosing interval and 931 ± 181 mg/dl for the 4- week dosing interval, comparable to the results from the pivotal study. Treatment of Immune Thrombocytopenic Purpura Pharmacokinetic studies with Privigen were not performed in patients with chronic ITP. Treatment of Chronic Inflammatory Demyelinating Polyneuropathy Pharmacokinetic studies with Privigen were not performed in patients with CIDP. Page 22 of 40

23 STORAGE AND STABILITY Privigen, Immune Globulin Intravenous (Human), can be stored either in the refrigerator or at room temperature (at +2 C to +25 C) until the expiration date printed on the outer carton and vial label. Do not freeze. Keep Privigen in its original carton to protect it from light. The shelf life of Privigen is 36 months. SPECIAL HANDLING INSTRUCTIONS Privigen, Immune Globulin Intravenous (Human), is a clear or slightly opalescent, colorless to pale yellow solution. As with all parenteral solutions, Privigen should be inspected visually for particulate matter and discoloration prior to administration. Do not use if the solution is cloudy or contains particulates. Any solution that has been frozen must not be used. DO NOT SHAKE. Do not mix Privigen with other IVIG products or other intravenous medications. If necessary, Privigen can be diluted with D5W. If large doses of Privigen are to be administered, several vials may be pooled using aseptic technique. The Privigen vial is for single use only. Once the vial has been entered under aseptic conditions, its contents should be used promptly. Because the solution contains no preservative, discard partially used product after 24 hours. Any unused product or waste material should be disposed of in accordance with local requirements. DOSAGE FORMS, COMPOSITION AND PACKAGING Privigen, Immune Globulin Intravenous (Human), is supplied in a single-use, tamper-evident vial containing the labeled amount of functionally active IgG. The components used in the packaging for Privigen are latex-free. The following dosage forms are available: Fill Size Grams IgG 25 ml 2.5 g 50 ml 5 g 100 ml 10 g 200 ml 20 g 400 ml 40 g Each vial has an integral suspension band and a label with two peel-off strips showing the product name, lot number, and expiration date. Composition: Human immunoglobulin: 100 g/l L-proline: 28.8 g/l (250 mmol/l) HCl and/or NaOH: for ph adjustment to 4.8 Water for Injection, USP: q.s. Page 23 of 40

24 PART II: SCIENTIFIC INFORMATION PHARMACEUTICAL INFORMATION Drug Substance Proper name: Chemical name: Immune Globulin Intravenous (Human) Immune Globulin Intravenous (Human) Molecular formula and molecular mass: 146,000 Da (IgG 1, IgG 2, and IgG 4 ), 170,000 Da (IgG 3 ) Structural formula: IgG has two identical light polypeptide chains and two identical heavy polypeptide chains, which are linked together with disulphide bonds. There are two intra-chain disulphide bonds in the light chain, one in the variable region and one in the constant region. There are four such bonds in the heavy chain. Each disulphide bond encloses a peptide loop of amino acid residues. These result in a series of globular regions with very similar secondary and tertiary structure. The peptide loops enclosed by the disulphide bonds represent the central portion of a domain of about 110 amino acid residues. In both the heavy and light chains the first of these domains corresponds to the variable region. In the light chain there is one additional domain and in the heavy chain three additional domains which make up the constant portion of the chain. It is variations in the amino acid sequence of the variable domains of the light and heavy chains that confer the specificity of immunoglobulins. The number and distribution of interchain disulphide bonds differ between the IgG subclasses with two for IgG 1 and IgG 4, four for IgG 2, and fifteen for IgG 3. Physicochemical properties: IgG-subclass distribution IgG % IgG % IgG 3 2.3% IgG 4 1.2% Page 24 of 40

25 Product Characteristics Privigen, Immune Globulin Intravenous (Human), is a ready-to-use, sterile, 10% protein liquid preparation of polyvalent human immunoglobulin G (IgG) for intravenous administration. Privigen is prepared from large pools of human plasma by a combination of cold ethanol fractionation, octanoic acid fractionation combined with a filter aid-assisted depth filtration, and anion exchange chromatography. In addition, the Privigen manufacturing process includes an immunoaffinity chromatography step that specifically reduces blood group A and B antibodies (isoagglutinins A and B). The IgG proteins are not subjected to heating or to chemical or enzymatic modification. The Fc and Fab functions of the IgG molecule are retained. Fab functions tested include antigen binding capacities, assessed with biochemical or biological assays. Fc functions tested include complement activation and Fc-receptor-mediated leukocyte activation (determined with complexed IgG). Scavenging/inhibition of immune complex-induced complement activation, an anti-inflammatory function of IVIGs, were greater in vitro with Privigen than with other marketed IVIG products. Privigen does not activate the complement system or prekallikrein in an unspecific manner. Privigen has a purity of at least 98% IgG, with trace amounts of IgA (no more than 25 mcg/ml of IgA levels), as well as other plasma proteins. The distribution of IgG subclasses is similar to that found in normal human plasma (see IgG-subclass distribution). Privigen is isotonic, with an osmolality of 320 mosmol/kg. Privigen contains no carbohydrate stabilizers (e.g., sucrose, maltose) and no preservative, and it has a low sodium content (1 meq/l or less). Privigen has a ph of 4.8 and contains 250 mmol/l of L-proline (a nonessential amino acid) as a stabilizer. The low ph and the presence of L-proline inhibit oxidative reactions (which cause discoloration) and IgG dimer formation (which is important for product tolerability). The IgG dimer content in IgG formulated with either 250 mmol/l L-proline (Privigen ) or 250 mmol/l glycine at a ph of 4.8 was evaluated after being stored at room temperature (+25ºC) for 60 days. The percentage of IgG dimers was 7.9% in Privigen and 11% in product formulated with glycine, representing a decrease in dimer content of approximately 30% in Privigen. All plasma used in the manufacture of Privigen is tested using FDA-licensed serological assays for hepatitis B surface antigen (HBsAg) and antibodies to HCV and HIV-1/2 as well as FDAlicensed Nucleic Acid Testing (NAT) for HCV and HIV-1 and found to be nonreactive (negative). Page 25 of 40

26 Viral Inactivation/Removal The manufacturing process for Privigen includes four steps that have been shown to reduce the risk of virus transmission in an additive manner. Octanoic acid fractionation, combined with a filter aid-assisted depth filtration, effectively eliminates enveloped viruses that are potentially present in the starting material. Dedicated virus clearance steps include ph 4 incubation to inactivate enveloped viruses and B19V 17 and virus filtration to remove by size exclusion both enveloped and non-enveloped viruses as small as approximately 20 nanometers. An additional depth filtration step removes residual non-igg proteins and contributes to the virus reduction capacity. These steps have been independently validated in a series of in vitro experiments for their capacity to inactivate and/or remove both enveloped and non-enveloped viruses. Table 9 shows the virus clearance during the manufacturing process for Privigen, expressed as the mean log 10 reduction factor (LRF). Table 9: Virus Inactivation/Removal in Privigen HIV-1 PRV BVDV WNV EMCV MVM [B19V] Virus property Genome RNA DNA RNA RNA RNA DNA Envelope Yes Yes Yes Yes No No Size (nm) Manufacturing step Mean LRF Octanoic acid fractionation 4.6* 6.3* 6.0* >7.4* 1.0** 1.4** ph 4 incubation >7.8 nt [>5.0] Depth filtration Virus filtration > Overall reduction (log 10 units) > HIV-1, human immunodeficiency virus type 1, a model for HIV-1 and HIV-2; PRV, pseudorabies virus, a nonspecific model for large enveloped DNA viruses (e.g., herpes virus); BVDV, bovine viral diarrhea virus, a model for hepatitis C virus; WNV, West Nile virus; EMCV, encephalomyocarditis virus, a model for hepatitis A virus; MVM, minute virus of mice, a model for a small highly resistant non-enveloped DNA virus (e.g., parvovirus); B19V, B19 virus; LRF, log 10 reduction factor; nt: not tested. * Given that the octanoic acid fractionation includes depth filtration, partitioning at this step and the step designated depth filtration shares partially overlapping mechanisms. Hence, these values were not accounted for in the overall LRF. ** Values less than 1.5 log 10 are not considered a significant reduction and are not accounted for in the overall LRF. The B19V value 18 is not accounted for in the overall LRF. The manufacturing process was also investigated for its capacity to decrease the infectivity of an experimental agent of TSE, considered a model for CJD and its variant vcjd. 18 Several of the production steps have been shown to decrease TSE infectivity of an experimental model agent. TSE reduction steps include octanoic acid fractionation combined with a filter aid-assisted depth filtration (>6.4 log 10 ), depth filtration (2.6 log 10 ), and virus filtration (>5.8 log 10 ). These studies provide reasonable assurance that low levels of vcjd/cjd agent infectivity, if present in the starting material, would be removed. Page 26 of 40